tbuckley/cabot-search huggingface dataset:
Letter to the Editor: Insurance should cover vancomycin for primary sclerosing cholangitis
Authors: Ahmad H. Ali, Cynthia W. Buness, Ryan Fischer, Gerald J. Holtmann, Ayesha Shah, Peter Lewindon, Shamita Shah, Amol S. Ragnekar, Amy E. Taylor, Aparna Goel, Kenneth L. Cox, Leina Alrabadi, Steve Wadsworth, Sakil S. Kulkarni, Keith D. Lindor
Journal: Hepatology (2023)

To the editor, Health care insurers should cover the costs of oral vancomycin (OV) for the treatment of primary sclerosing cholangitis (PSC). AASLD's 2022 PSC Practice Guidance (Guidance)1 combined with the AASLD separate Supporting Statement2 are helpful. While the Guidance doesn't recommend OV for PSC.1 AASLD published a separate Supporting Statement stating: "The Guidance notes the insufficiency of the evidence and accordingly does not make a recommendation for or against the use of OV for the treatment of PSC. In the absence of a definitive clinical trial, the decision to use an off-label medication should remain between the doctor and the patient. Larger clinical trials or studies are needed to conclusively assess the efficacy and safety of vancomycin in PSC. Although there is not sufficient evidence to make a formal recommendation regarding the use of OV for PSC, it should not be used as justification to restrict coverage of this treatment if a physician feels it is the right course of action". Although large, controlled trials are not yet completed, 2 small, controlled trials and evidence from multiple cohort studies are summarized in a systematic review and meta-analysis demonstrating OV has beneficial effects on liver functions in PSC patients. These robust findings are further supported by a recent pediatric/adult cohort study where OV showed benefits in lowering cholestatic enzymes and improving MRCP findings of bile duct dilatation and stenoses.3,4 This might translate to fewer liver transplants, fewer hospitalizations for acute cholangitis, and other expensive consequences of not treating this devastating disease. In addition, OV has beneficial effects on PSC-associated colitis with the improvement of diarrhea and other symptoms.3,4 The medical community desires better treatments at lower costs. For responsive PSC/inflammatory bowel disease patients, insurers stand to benefit financially by allowing OV to be substituted for biologic drugs. The beneficial effects of OV on colitis are its most reliable effects. Biologics typically cost 5 times more than OV, and the gain over placebo is small. Some surgeries might also be avoided; our patients have avoided colectomies with OV. While OV does not work for all PSC patients, no other treatment (besides liver transplantation) has proven effective in even a subgroup of PSC patients. Medical and financial reasons for insurers to cover OV for PSC are compelling as long as the physician and patient can demonstrate that OV benefits the patient.
The road to pandemic recovery: Tracking COVID-19’s impact on cirrhosis care and outcomes among 111,558 Veterans
Authors: Adeyinka C. Adejumo, Vera Yakovchenko, Timothy R. Morgan, Patrick Spoutz, Linda Chia, Jasmohan S. Bajaj, Michael F. Chang, Jason A. Dominitz, Shari S. Rogal
Journal: Hepatology (2023)

Background &amp; Aims: This study aimed to evaluate quarterly trends in process and health outcomes among Veterans with cirrhosis and assess the factors associated with cirrhosis outcomes before and during the COVID-19 pandemic. Approach &amp; Results: US Veterans with cirrhosis were identified using the Veterans Health Administration Corporate Data Warehouse. Quarterly measures were evaluated from September 30, 2018, through March 31, 2022, including twice yearly screening for hepatocellular carcinoma (HCC-6), new HCC, surveillance for or treatment of esophageal varices, variceal bleeding, all-cause hospitalization, and mortality. Joinpoint analyses were used to assess the changes in trends over time. Logistic regression models were used to identify the demographic and medical factors associated with each outcome over time. Among 111,558 Veterans with cirrhosis with a mean Model for End-stage Liver Disease-Sodium of 11±5, rates of HCC-6 sharply declined from a prepandemic peak of 41%, to a nadir of 28%, and rebounded to 36% by March 2022. All-cause mortality did not significantly change over the pandemic, but new HCC diagnosis, EVST, variceal bleeding, and all-cause hospitalization significantly declined over follow-up. Quarterly HCC diagnosis declined from 0.49% to 0.38%, EVST from 50% to 41%, variceal bleeding from 0.15% to 0.11%, and hospitalization from 9% to 5%. Rurality became newly, significantly associated with nonscreening over the pandemic (aOR for HCC−6=0.80, 95% CI 0.74 to 0.86; aOR for EVST=0.95, 95% CI 0.90 to 0.997). Conclusions: The pandemic continues to impact cirrhosis care. Identifying populations at the highest risk of care disruptions may help to address ongoing areas of need.
In Vivo Dissection of Chamber-Selective Enhancers Reveals Estrogen-Related Receptor as a Regulator of Ventricular Cardiomyocyte Identity
Authors: Yangpo Cao, Xiaoran Zhang, Brynn N. Akerberg, Haiyun Yuan, Tomoya Sakamoto, Feng Xiao, Nathan J. VanDusen, Pingzhu Zhou, Mason E. Sweat, Yi Wang, Maksymilian Prondzynski, Jian Chen, Yan Zhang, Peizhe Wang, Daniel P. Kelly, William T. Pu
Journal: Circulation (2023)

Background: Cardiac chamber-selective transcriptional programs underpin the structural and functional differences between atrial and ventricular cardiomyocytes (aCMs and vCMs). The mechanisms responsible for these chamber-selective transcriptional programs remain largely undefined. Methods: We nominated candidate chamber-selective enhancers (CSEs) by determining the genome-wide occupancy of 7 key cardiac transcription factors (GATA4, MEF2A, MEF2C, NKX2-5, SRF, TBX5, TEAD1) and transcriptional coactivator P300 in atria and ventricles. Candidate enhancers were tested using an adeno-associated virus–mediated massively parallel reporter assay. Chromatin features of CSEs were evaluated by performing assay of transposase accessible chromatin sequencing and acetylation of histone H3 at lysine 27-HiChIP on aCMs and vCMs. CSE sequence requirements were determined by systematic tiling mutagenesis of 29 CSEs at 5 bp resolution. Estrogen-related receptor (ERR) function in cardiomyocytes was evaluated by Cre-loxP–mediated inactivation of ERRα and ERRγ in cardiomyocytes. Results: We identified 134 066 and 97 506 regions reproducibly occupied by at least 1 transcription factor or P300, in atria or ventricles, respectively. Enhancer activities of 2639 regions bound by transcription factors or P300 were tested in aCMs and vCMs by adeno-associated virus–mediated massively parallel reporter assay. This identified 1092 active enhancers in aCMs or vCMs. Several overlapped loci associated with cardiovascular disease through genome-wide association studies, and 229 exhibited chamber-selective activity in aCMs or vCMs. Many CSEs exhibited differential chromatin accessibility between aCMs and vCMs, and CSEs were enriched for aCM- or vCM-selective acetylation of histone H3 at lysine 27–anchored loops. Tiling mutagenesis of 29 CSEs identified the binding motif of ERRα/γ as important for ventricular enhancer activity. The requirement of ERRα/γ to activate ventricular CSEs and promote vCM identity was confirmed by loss of the vCM gene profile in ERRα/γ knockout vCMs. Conclusions: We identified 229 CSEs that could be useful research tools or direct therapeutic gene expression. We showed that chamber-selective multi–transcription factor, P300 occupancy, open chromatin, and chromatin looping are predictive features of CSEs. We found that ERRα/γ are essential for maintenance of ventricular identity. Finally, our gene expression, epigenetic, 3-dimensional genome, and enhancer activity atlas provide key resources for future studies of chamber-selective gene regulation.
Correction to: Effect of postextubation noninvasive ventilation with active humidification vs high-flow nasal cannula on reintubation in patients at very high risk for extubation failure: a randomized trial
Authors: Gonzalo Hernández, Irene Paredes, Francisco Moran, Marcos Buj, Laura Colinas, María Luisa Rodríguez, Alfonso Velasco, Patricia Rodríguez, María José Pérez-Pedrero, Fernando Suarez-Sipmann, Alfonso Canabal, Rafael Cuena, Lluis Blanch, Oriol Roca
Journal: Intensive Care Medicine (2023)
Management of children and adolescents with chronic myeloid leukemia in blast phase: International pediatric CML expert panel recommendations
Authors: Stephanie Sembill, Maria Ampatzidou, Sonali Chaudhury, Michael Dworzak, Krzysztof Kalwak, Axel Karow, Alexander Kiani, Manuela Krumbholz, Maaike Luesink, Nora Naumann-Bartsch, Barbara De Moerloose, Michael Osborn, Kirk R. Schultz, Petr Sedlacek, Fiorina Giona, Christian Michel Zwaan, Hiroyuki Shimada, Birgitta Versluijs, Frederic Millot, Nobuko Hijiya, Meinolf Suttorp, Markus Metzler
Journal: Leukemia (2023)

Abstract Treatment of chronic myeloid leukemia has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs), and treatment guidelines based on numerous clinical trials are available for chronic phase disease. However for CML in the blast phase (CML-BP), prognosis remains poor and treatment options are much more limited. The spectrum of treatment strategies for children and adolescents with CML-BP has largely evolved empirically and includes treatment principles derived from adult CML-BP and pediatric acute leukemia. Given this heterogeneity of treatment approaches, we formed an international panel of pediatric CML experts to develop recommendations for consistent therapy in children and adolescents with this high-risk disease based on the current literature and national standards. Recommendations include detailed information on initial diagnosis and treatment monitoring, differentiation from Philadelphia-positive acute leukemia, subtype-specific selection of induction therapy, and combination with tyrosine kinase inhibitors. Given that allogeneic hematopoietic stem cell transplantation currently remains the primary curative intervention for CML-BP, we also provide recommendations for the timing of transplantation, donor and graft selection, selection of a conditioning regimen and prophylaxis for graft-versus-host disease, post-transplant TKI therapy, and management of molecular relapse. Management according to the treatment recommendations presented here is intended to provide the basis for the design of future prospective clinical trials to improve outcomes for this challenging disease.
STING trafficking as a new dimension of immune signaling
Authors: Devon Jeltema, Kennady Abbott, Nan Yan
Journal: The Journal of Experimental Medicine (2023)

The cGAS-STING pathway is an evolutionarily conserved immune signaling pathway critical for microbial defense. Unlike other innate immune pathways that largely rely on stationary cascades of signaling events, STING is highly mobile in the cell. STING is activated on the ER, but only signals after it arrives on the Golgi, and then it is quickly degraded by the lysosome. Each step of STING trafficking through the secretory pathway is regulated by host factors. Homeostatic STING trafficking via COPI-, COPII-, and clathrin-coated vesicles is important for maintaining baseline tissue and cellular immunity. Aberrant vesicular trafficking or lysosomal dysfunction produces an immune signal through STING, which often leads to tissue pathology in mice and humans. Many trafficking-mediated diseases of STING signaling appear to impact the central nervous system, leading to neurodegeneration. Therefore, STING trafficking introduces a new dimension of immune signaling that likely has broad implications in human disease.
Oxytocin receptor is not required for social attachment in prairie voles
Authors: Kristen M. Berendzen, Ruchira Sharma, Maricruz Alvarado Mandujano, Yichao Wei, Forrest D. Rogers, Trenton C. Simmons, Adele M.H. Seelke, Jessica M. Bond, Rose Larios, Nastacia L. Goodwin, Michael Sherman, Srinivas Parthasarthy, Isidero Espineda, Joseph R. Knoedler, Annaliese Beery, Karen L. Bales, Nirao M. Shah, Devanand S. Manoli
Journal: Neuron (2023)
Structure of the Inmazeb cocktail and resistance to Ebola virus escape
Authors: Vamseedhar Rayaprolu, Benjamin O Fulton, Ashique Rafique, Emilia Arturo, Dewight Williams, Chitra Hariharan, Heather Callaway, Amar Parvate, Sharon L Schendel, Diptiben Parekh, Sean Hui, Kelly Shaffer, Kristen E Pascal, Elzbieta Wloga, Stephanie Giordano, Nicole Negron, Min Ni, Richard Copin, Gurinder S Atwal, Matthew Franklin, Ruth Mabel Boytz, Callie Donahue, Robert Davey, Alina Baum, Christos A Kyratsous, Erica Ollmann Saphire
Journal: Cell Host & Microbe (2023)

Monoclonal antibodies can provide important pre- or post-exposure protection against infectious disease for those not yet vaccinated or in individuals that fail to mount a protective immune response after vaccination. Inmazeb (REGN-EB3), a three-antibody cocktail against Ebola virus, lessened disease and improved survival in a controlled trial. Here, we present the cryo-EM structure at 3.1 Å of the Ebola virus glycoprotein, determined without symmetry averaging, in a simultaneous complex with the antibodies in the Inmazeb cocktail. This structure allows the modeling of previously disordered portions of the glycoprotein glycan cap, maps the non-overlapping epitopes of Inmazeb, and illuminates the basis for complementary activities and residues critical for resistance to escape by these and other clinically relevant antibodies. We further provide direct evidence that Inmazeb protects against the rapid emergence of escape mutants, whereas monotherapies even against conserved epitopes do not, supporting the benefit of a cocktail versus a monotherapy approach.
Phase I Study and Cell-Free DNA Analysis of T-DM1 and Metronomic Temozolomide for Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases
Authors: Sarah Jenkins, Wei Zhang, Seth M. Steinberg, Darryl Nousome, Nicole Houston, Xiaolin Wu, Terri S. Armstrong, Eric Burton, Dee Dee Smart, Ritu Shah, Cody J. Peer, Brett Mozarsky, Oluwatobi Arisa, William D. Figg, Tito R. Mendoza, Elizabeth Vera, Priscilla Brastianos, Scott Carter, Mark R. Gilbert, Carey K. Anders, Roisín M. Connolly, Carol Tweed, Karen L. Smith, Imran Khan, Stanley Lipkowitz, Patricia S. Steeg, Alexandra S. Zimmer
Journal: Clinical Cancer Research (2023)

Preclinical data showed that prophylactic, low-dose temozolomide (TMZ) significantly prevented breast cancer brain metastasis. We present results of a phase I trial combining T-DM1 with TMZ for the prevention of additional brain metastases after previous occurrence and local treatment in patients with HER2+ breast cancer.Eligible patients had HER2+ breast cancer with brain metastases and were within 12 weeks of whole brain radiation therapy (WBRT), stereotactic radiosurgery, and/or surgery. Standard doses of T-DM1 were administered intravenously every 21 days (3.6 mg/kg) and TMZ was given orally daily in a 3+3 phase I dose escalation design at 30, 40, or 50 mg/m2, continuously. DLT period was one 21-day cycle. Primary endpoint was safety and recommended phase II dose. Symptom questionnaires, brain MRI, and systemic CT scans were performed every 6 weeks. Cell-free DNA sequencing was performed on patients' plasma and CSF.Twelve women enrolled, nine (75%) with prior SRS therapy and three (25%) with prior WBRT. Grade 3 or 4 AEs included thrombocytopenia (1/12), neutropenia (1/12), lymphopenia (6/12), and decreased CD4 (6/12), requiring pentamidine for Pneumocystis jirovecii pneumonia prophylaxis. No DLT was observed. Four patients on the highest TMZ dose underwent dose reductions. At trial entry, 6 of 12 patients had tumor mutations in CSF, indicating ongoing metastatic colonization despite a clear MRI. Median follow-up on study was 9.6 m (2.8-33.9); only 2 patients developed new parenchymal brain metastases. Tumor mutations varied with patient outcome.Metronomic TMZ in combination with standard dose T-DM1 shows low-grade toxicity and potential activity in secondary prevention of HER2+ brain metastases.
Association Between Preapproval Confirmatory Trial Initiation and Conversion to Traditional Approval or Withdrawal in the FDA Accelerated Approval Pathway
Authors: Mahnum Shahzad, Huseyin Naci, Anita K. Wagner
Journal: JAMA (2023)

This study examines the Food and Drug Administration’s accelerated approval pathway and whether preapproval initiation was associated with faster conversion to traditional approval or withdrawal for drugs with nononcology indications.
Perceptions of Prehospital Care for Patients With Limited English Proficiency Among Emergency Medical Technicians and Paramedics
Authors: Kathryn M. Stadeli, Dylan Sonett, Kelsey M. Conrick, Megan Moore, Matthew Riesenberg, Eileen M. Bulger, Hendrika Meischke, Monica S. Vavilala
Journal: JAMA Network Open (2023)

Patients with limited English proficiency (LEP) experience disparities in prehospital care. On-scene interactions between patients with LEP and emergency medical services (EMS) providers (ie, firefighters/emergency medical technicians [EMTs] and paramedics) are critical to high-quality care and have been minimally explored.To identify EMS-perceived barriers and facilitators to providing high-quality prehospital care for patients with LEP.In this qualitative study, semi-structured focus groups were conducted with firefighters/EMTs and paramedics with all levels of experience from urban areas with a high proportion of residents with LEP from July to September 2018. Data were analyzed from July 2018 to May 2019.Providing prehospital care for patients with LEP.The main outcomes were barriers and facilitators to prehospital care for patients with LEP, assessed using thematic analysis. Four domains of interest were examined: (1) overall impressions of interactions with patients with LEP, (2) barriers and facilitators to communication, (3) barriers and facilitators to providing care, and (4) ideas for improving prehospital care for patients with LEP.Thirty-nine EMS providers participated in 8 focus groups: 26 firefighters/EMTs (66%) and 13 paramedics (33%). The median age of participants was 46 years (range, 23-63 years), and 35 (90%) were male. Participants described barriers to optimal care as ineffective interpretation, cultural differences, high-stress scenarios (eg, violent events), unclear acuity of patient's condition, provider bias, and distrust of EMS. Perceived facilitators to optimal care included using an on-scene interpreter, high-acuity disease, relying on objective clinical findings, building trust and rapport, and conservative decision-making regarding treatment and transport. Providers reported transporting most patients with LEP to hospitals regardless of illness severity due to concern for miscommunication and unrecognized problems. Better speed and technology for interpretation, education for communities and EMS providers, and community-EMS interactions outside emergencies were cited as potential strategies for improvement.In this study, EMS providers described many barriers to high-quality care during prehospital emergency response for patients with LEP yet were unaware that these barriers impacted quality of care. Barriers including ineffective interpretation, provider bias, distrust of EMS, and cultural differences may contribute to outcome disparities and overutilization of resources. Future work should focus on the development of targeted interventions to improve modifiable barriers to care, such as improving interpretation and cultural humility and increasing trust.
Association of State Insurance Mandates for Fertility Treatment With Multiple Embryo Transfer After Preimplantation Genetic Testing for Aneuploidy
Authors: Bronwyn S. Bedrick, Katelin B. Nickel, Joan K. Riley, Tarun Jain, Emily S. Jungheim
Journal: JAMA Network Open (2023)

Multiple gestation is one of the biggest risks after in vitro fertilization (IVF), largely due to multiple embryo transfer (MET). Single embryo transfer (SET) uptake has increased over time and has been attributed to various factors, such as mandated insurance coverage for IVF and preimplantation genetic testing for aneuploidy (PGT-A).To investigate whether mandates for IVF insurance coverage are associated with decreased use of MET after PGT-A.This cohort study was conducted using data on embryo transfers reported to the Society for Assisted Reproductive Technology between 2014 and 2016. Data were analyzed from January to October 2021.State-mandated coverage for fertility treatment and type of cycle transfer performed (PGT-A, untested fresh, and untested frozen).Use of MET compared with SET, live birth, and live birth of multiples.There were 110 843 embryo transfers (mean [SD] patient age, 34.0 [4.5] years; 5520 individuals identified as African American [5.0%], 10 035 as Asian [9.0%], 5425 as Hispanic [4.9%], 45 561 as White [41.1%], and 44 302 as other or unknown race or ethnicity [40.0%]); 17 650 transfers used embryos that underwent PGT-A. Overall, among transferred embryos that had PGT-A, there were 9712 live births (55.0%). The odds of live birth were 70% higher with MET vs SET after frozen embryo transfer with PGT-A (OR, 1.70; 95% CI, 1.61-1.78), but the risk of multiples was 5 times higher (OR, 5.33; 95% CI, 5.22-5.44). The odds of MET in cycles with PGT-A in states with insurance mandates were 24% lower than in states without mandates (OR, 0.76; 95% CI, 0.68-0.85).This study found that despite the promise of using SET with PGT-A, MET after PGT-A was not uncommon. This practice was more common in states without insurance mandates and was associated with a high risk of multiples.